Biologics Feature

Scaffold-Free MSC Cartilage Repair Passes Major Test

Biloine W. Young • Tue, January 9th, 2018

The search goes on—for a biologic solution to damaged or worn-down cartilage.

Now a group of researchers at Osaka University have passed their first-in-man test of a novel, scaffold-free mesenchymal stem cells (MSC) solution. One year after implantation, healthy cartilage.

Here are the before and after photos.

Implantation / Source: Osaka University

What makes this approach so innovative is that is uses only allogenic MSC cells in a novel solution (supplier Twocells Company Ltd.) and then applies mechanical forces to “firm” up the solution into an injectable living cell treatment that will adhere to the knee and, without requiring a scaffold, differentiate and grow into cartilage repair tissue.

The lead investigators at Osaka University have progressed to Phase III in their clinical trial and this first-in-man test is highly encouraging.

Importantly, this is a direct result of the stem cell bank at Osaka University’s Medical Center for Translational Research.

Researchers Norimasa Nakamura, Hideki Yoshikawa, and Yoshiki Sawa tested this novel approach which, in some ways, mimics nature’s approach to driving progenitor cell differentiation. The Osaka team started with cell bank sourced MSCs, cultured them using a new form of cell culture solution, then, in a move which mirrors the natural forces which signal progenitor cells to differentiate—applied mechanical forces to the culturing cells and created a scaffold-free, three-dimensional gel-like, injectable living tissue.

As this first-in-man test demonstrated, the material can repair cartilage.

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Recalcitrant Stem Cells Meet Their Match

Biloine W. Young • Sun, September 22nd, 2013

First the problem—then a throw of the dart at a solution. As every patient with painful joints knows, injuries affecting cartilage are notoriously hard to treat because cartilage cannot heal itself. For more than a decade researchers have been trying to unlock the code to using stem cells to repair joints and cartilage.

However, the stem cells have not been cooperating. Stem cell based cartilage regeneration is still in its infancy because stem cells will not stay in a desired tissue site and remain alive. As Benjamin Holmes, a writer for Nanotechweb noted, it is also difficult for researchers to control stem cells so-called chondrogenic differentiation.

Labs around the world have been looking at innovative nanomaterials in an attempt to create complex, biomimetic composites and structures called "scaffolds" that can support and direct how stem cells form and eventually develop into fully formed tissue. The hope was that these nanomaterials would mimic the physical and chemical characteristics of human tissue extracellular matrix and provide a structural as well as functional framework for cell growth.

A team led by Lijie Grace Zhang, Ph.D. and Michael Keidar, Ph.D., at George Washington University, Washington, D.C., may have done that. They employed carbon nanotubes to modify polymeric scaffolds, added nanoscale surface roughness to these structures, and modulated their mechanical properties. The idea (and the hope) was that these nanotubes could be incorporated into existing polymer networks so that the scaffolds’ properties would match the characteristics of the human tissue extracellular matrix which makes up cartilage. They found that scaffolds made from these fibers had mechanical properties that were virtually the same as native articulate cartilage.

To quote from the Nanotechweb article, “cell studies with human bone marrow derived stem cells showed that biomimetic nano/micro scaffolds made with H2 treated MWCNTs [multi-walled carbon nanotubes] not only outperformed un-purified MWCNT scaffolds, but also greatly outperformed plain PLLA [poly-L-lactide] scaffolds. Stem cells not only grew better on H2 CNT [carbon nanotubes] scaffolds, but also regenerated more cartilage in two weeks. This means that CNT-modified polymer scaffolds could usher in a new era in cartilage tissue engineering, and foster a whole new class of nanocomposite materials for tissue regeneration and stem cell therapies.”

Natural Fibers Good Stem Cell Matrix

Biloine W. Young • Thu, May 16th, 2013

Stem cells need a partner if they are to be biologically effective as regenerators of cartilage tissue. University of Bristol researchers in the United Kingdom believe they may have found that partner. In a study published in Biomacromolecules they explored the feasibility of using naturally occurring fibers such as cellulose and silk for stem cell scaffolds—the matrix to which stem cells can cling as they grow.

The team treated blends of silk and cellulose for use as a tiny scaffold that allows adult connective tissue stem cells to form into a preliminary form of chondrocytes—the cells that make healthy tissue cartilage—and secrete extracellular matrix similar to natural cartilage.

Wael Kafienah, M.D., lead author from the University's School of Cellular and Molecular Medicine, said: "We were surprised with this finding, the blend seems to provide complex chemical and mechanical cues that induce stem cell differentiation into preliminary form of chondrocytes without need for biochemical induction using expensive soluble differentiation factors. This new blend can cut the cost for health providers and makes progress towards effective cell-based therapy for cartilage repair a step closer."

Sameer Rahatekar, Ph.D., lead author from the University's Advanced Composite Centre for Innovation and Science, added: "We used ionic liquids for the first time to produce cellulose and silk scaffolds for stem cells differentiation. These liquids are effective in dissolving biopolymers and are environmentally benign compared to traditional solvents used for processing of cellulose and silk."

The teams are currently working on the fabrication of 3D structures from the blend suitable for implantation in patients’ joints. Future studies will focus on understanding the peculiar interactions between the blend and stem cells towards refining the quality of the regenerated cartilage. Over 20 million people in Europe suffer from osteoarthritis which can lead to extensive damage to the knee and hip cartilage.

Horses & Humans Cartilage Test Subjects

Biloine W. Young • Tue, April 28th, 2015

Research institutes from New Zealand and South Korea are joining forces to find viable treatment options for both humans and horses that lose cartilage. (Horses have knee cartilage that is similar in shape and load-bearing function to that of humans.) The researchers hope to regenerate degraded cartilage in people before it leads to osteoarthritis.

The institutions involved are Massey University and the University of Otago in New Zealand as well as Seoul National University, the Korean Institute of Science and Technology, Advanced Institutes of Convergence Technology and Kangstem Biotech in Korea. All are part of the newly-established strategic research partnership, funded by the Ministry of Business, Innovation and Employment.

The scientists involved aim to create specialized 3-D bio-scaffolds that mimic the texture and shape of cartilage in the knee joint. They plan to inject the scaffolds with stem cells obtained from umbilical cord blood to grow chondrocytes—the cells that are found in, and create, healthy cartilage. The chondrocytes and their supporting scaffold will then be implanted into the knee joints of horses to see if they will regenerate the cartilage there.

Massey University Professor of equine clinical studies Chris Riley, BSc, BVSc(Hons), MSc, Ph.D. says the strength of the partnership lies in bringing together scientists from different disciplines. “Innovation comes from sharing research capabilities. Massey brings expertise in animal research and animal modeling with the University of Otago developing the scaffolds and researchers from Seoul working on innovations in the isolation of stem cells from cord blood.”

Bone and Cartilage Creating Cell Discovered

Biloine W. Young • Mon, February 9th, 2015

Scientists at Columbia University Medical Center (CUMC) have identified a stem cell in the bone marrow of mice that is capable of regenerating both bone and cartilage. They report their study (“Gremlin 1 Identifies a Skeletal Stem Cell with Bone, Cartilage, and Reticular Stromal Potential”) in the online issue of Cell.

They discovered the cells, called osteochondroreticular (OCR) stem cells, by tracking a protein expressed by the cells. Using this as a marker, the researchers found that OCR cells self-renew and generate key bone and cartilage cells, including osteoblasts and chondrocytes. The researchers also showed that OCR stem cells, when transplanted to a fracture site, contribute to bone repair.

“We demonstrate here that expression of the bone morphogenetic protein (BMP) antagonist gremlin 1 defines a population of osteochondroreticular (OCR) stem cells in the bone marrow, ” wrote the investigators. “OCR stem cells self-renew and generate osteoblasts, chondrocytes, and reticular marrow stromal cells, but not adipocytes. OCR stem cells are concentrated within the metaphysis of long bones not in the perisinusoidal space and are needed for bone development, bone remodeling, and fracture repair.”

"We are now trying to figure out whether we can persuade these cells to specifically regenerate after injury. If you make a fracture in the mouse, these cells will come alive again, generate both bone and cartilage in the mouse—and repair the fracture. The question is, could this happen in humans, " said Siddhartha Mukherjee, M.D., Ph.D., an assistant professor of medicine at CUMC and a senior author of the study.

The researchers believe that OCR stem cells will be found in human bone tissue, as mice and humans have similar bone biology. "Our findings raise the possibility that drugs or other therapies can be developed to stimulate the production of OCR stem cells and improve the body's ability to repair bone injury—a process that declines significantly in old age, " said Timothy C. Wang, M.D., the Dorothy L. and Daniel H. Silberberg Professor of Medicine at CUMC, who initiated this research.

The study also showed that the adult OCRs are distinct from mesenchymal stem cells (MSCs), which play a role in bone generation during development and adulthood.

Iron-Laced Stem Cells

Biloine W. Young • Wed, July 23rd, 2014

Intravenous iron can be used to effectively label stem cell transplants so they can be tracked in target tissues—such as arthritic joints—according to a recent study conducted at Stanford University School of Medicine.

According to the study, intravenous iron can be utilized to effectively label stem cell transplants so they can be tracked in target tissues using magnetic resonance imaging (MRI). As is widely understood, mesenchymal stem cells (MSCs) derived from bone marrow appear to have remarkable potential in the field of cell-based therapy and tissue regeneration.

Heike Daldrup-Link, M.D., associate professor at Stanford University School of Medicine, notes that investigators have long worked with transplanted MSCs to get them to repair damaged joints by promoting the generation of bone, cartilage and connective tissue.

The problem, as Daldrup-Link sees it is that when stem cells are transplanted they often die and disappear from the transplant site. To confirm that a transplant has been successful, the investigator must track the stem cells they have introduced into the body and find out where they are and what they are doing.

Present practice is to remove the stem cells from the donor and culture them with an iron oxide solution before transplanting them in the patient. This raises the risk of contamination of the stem cells. The Stanford researchers propose that the stem cells can be treated in vivo by giving the donor an iron supplement intravenously prior to the harvesting of the stem cells. Iron oxide, which can be tracked using magnetic resonance imaging (MRI), would be taken up by the donor cells including the stem cells that are due to be transplanted.

Researchers at Stanford University School of Medicine have tried this on rats and it worked. They injected the rats with ferumoxytol, an iron supplement approved for human use, 48 hours before extracting stem cells from their bone marrow. The uptake of iron by stem cells was found to be greater after administration of in vivo ferumoxytol than it had been with the conventional ex vivo-labeling technique.

They transplanted the stem cells into knee cartilage defects of seven rats and tracked them with MRIs for up to a month.